Recent studies have suggested that HIV-1 Tat should be considered as an important component of potential HIV vaccines. We propose investigating whether orally administered Tat can elicit systemic anti-Tat immune responses. We will express HIV-1 Tat in spinach. Following oral administration to mice, we will analyze systemic and mucosal humoral and cell-mediated reactivity to Tat. As suggested by preliminary data, and because of its ability to be taken up by cells and to bind to cell surface receptors, it is possible that native Tat could compromise the development of antiviral immunity. We therefore will analyze several Tat mutants that lack transactivating ability or the ability to be taken up by cells and determine whether they elicit a stronger immune response than wild type Tat. We will also determine whether either formulation improves the response to subsequent vaccination to a Tat-gpl20 DNA vaccine. These studies will provide important information on whether native or modified Tat should be included in an HIV vaccine and will provide data on the feasibility of oral administration of HIV antigens in edible plants.